Summary Regulators of Th2 inflammation at the barrier interface in chronic allergic diseases such as atopic dermatitis and asthma are not as well characterized as those in the initiation phase. Yet effector functions of leukocytes in the chronic phase of Th2 inflammation drive symptomatic human disease that results in immune pathology associated with much morbidity after usually asymptomatic allergen sensitization. Chemokines are chemotactic cytokines that control leukocyte recruitment and inflammation by binding specific receptors on target cells. We recently discovered that the human chemokine CCL18 is a novel agonist of the CCR8 receptor. CCL18 is a signature chemokine produced by Th2 cytokine differentiated IL-4 spectrum macrophages, M(IL-4)s, also known as alternatively activated or M2 macrophages. CCL18 is associated with several chronic and eosinophilic inflammatory human diseases, and is one of the most highly induced chemokines in lesional atopic dermatitis skin. M(IL-4) interactions with the recently discovered Group 2 Innate Lymphoid Cells (ILC2) have been shown to facilitate eosinophilic inflammation. CCR8 is also a top signature gene of the mouse ILC2 transcriptome. Recently IL-4R? blockade, which inhibits M(IL-4) differentiation, resulted in striking clinical improvement of treatment refractory atopic dermatitis that highly correlated with suppression of CCL18. Yet, whether and how CCL18 and M(IL-4)s sustain chronic atopic dermatitis pathology is not known. Our published and new preliminary data lead us to hypothesize that though M(IL-4)s are anti-inflammatory in acute inflammation, they undergo pathogenic transformation at barrier interfaces to become pro-inflammatory in chronic inflammation, and partly through the CCR8 pathway and other mediators, and local interactions with cells such as ILC2s sustain chronic eosinophilic allergic inflammation in the skin. To test this hypothesis we will use a model of chronic allergic dermatitis. We also discovered a novel mouse chemokine agonist of the CCR8 receptor that is a functional analog of CCL18. We thus propose to: (1) Determine if M(IL-4)s are crucial for chronic allergic inflammation and identify mechanisms by which they do so, and if this is regulated by the CCR8 pathway; and (2) Define how ILC2s contribute to chronic allergic inflammation and if this is mediated by the CCR8 pathway. We will determine the clinical correlates of the studies proposed in Aims 1 and 2 using clinical specimens from individuals with eczema that will be compared to healthy controls.